The present application concerns substituted sapphyrins and sapphyrin derivatives. Sapphyrin, first discovered serendipitously by Woodward, ((a) First reported by R. B. Woodward at the Aromaticity Conference, Sheffield, U.K. 1966; (b) Bauer, V. J.; Clive, D. R.; Dolphin D.; Paine, J.B. III; Harris, F. L.; King, M.M.; Loder, J.; Wang, S.-W.C.; Woodward, R. B. J. Am. Chem. Soc. 1983, 105, 6429-6436) is one of the more intriguing products to emerge from initial studies directed towards the synthesis of Vitamin B.sub.12. (Bauer et al., J. Am. Chem. Soc., 1983; Broadhurst, M.J.; Grigg, R.; Johnson, A. W. J. Chem. Soc. Perkin Trans. 1, 1972, 2111-2116; Grigg, R. in The Porphyrins, Dolphin, D., Ed.; Academic Press: New York; 1978, Vol. II, pp. 327-391.) It is a 22 pi-electron pentapyrrolic macrocycle that forms a dark blue solid (hence the name sapphyrin) which exhibits an intense Soret-like band at about 450 nm (CHCl.sub.3) along with weaker Q-type transitions in the 620 to 690 nm region. These optical properties along with the presence of a large central cavity, which could possibly serve for metal binding, suggest that sapphyrin and its derivatives should be useful for many technologies, including a variety of emerging biomedical applications, notably photodynamic therapy (PDT) (For overviews of PDT see: (a) Gomer, C.J. Photochem Photobiol. 1987, 46, 561-562 (special issue on this topic); (b) Dahlman, A.; Wile, A.G.; Burns, R. G.; Mason, G. R.; Johnson, F. M.; Berns, M.W. Cancer Res. 1983, 43, 430-434; (c) Dougherty, T.J. in Methods in Porphyrin Photosensitization, Kessel, D., Ed.; Plenum Press: New York, 1985; pp. 313-328; (d) Dougherty, T. J. Photochem. Photobiol. 1987, 45, 879-889; (e) Gomer, C. J. Semin. Hematol. 1989, 26, 27-34; (f) Manyak, M.J.; Russo, A.; Smith, T.D. and Glatstein, E. J. Clin. Oncol. 1988, 6 p. 380-391) where long wavelength (&gt;680 nm) absorptions are desired, (For a specific discussion of the desirability of obtaining long-wavelength photosensitizers see Kreimer-Birnbaum, M. Seminars in Hematology 1989, 26, 157-173) and magnetic resonance imaging enhancement (MRI) where chelation of highly paramagnetic metal cations such as gadolinium(III) would be particularly worthwhile. (For an introductory discussion of MRI contrast agents see: Tweedle, M.F.; Brittain, H.G.: Eckelman, W.C.; et al. in Magnetic Resonance Imaging, 2nd ed., Partain, C. L.; et al. Eds.; W. B. Saunders: Philadelphia; 1988, Vol 1., pp. 793-809. For a comprehensive review of paramagnetic MRI contrast agents see: Lauffer, R. B. Chem. Rev. 1987, 87, 901-927). However, in spite of being known for over 20 years, almost no work has been devoted to the systematic study of this intriguing "expanded porphyrin", (Grigg, R. in The Porphyrins, Dolphin, D., Ed.; Academic Pres: New York; 1978, Vol. II, pp. 327-391.) in part, perhaps, because of the tedious nature of the synthesis involved. For instance, to date, no well-characterized sapphyrin-based pentacoordinated metal complexes have been reported, although attempts to prepare these materials have been recorded. (Bauer, V. J.; Clive, D. R.; Dolphin, D.; Paine, J. B. III; Harris, F. L.; King, M. M.; Loder, J.; Wang, S.-W. C.; Woodward, R. B. J. Am. Chem. Soc. 1983, 105, 6429-6436). In fact, only tetracoordinated metal complexes have been prepared to date from these potentially pentadentate ligand systems. Moreover, in marked contrast to the far better studied 18 pi-electron porphyrins no structural information currently exists for this curious ring system in either its free-base or metalated forms. The present invention comprises an improved synthesis of sapphyrins, as well as the first crystallographic characterization of a sapphyrin.
The original sapphyrin synthesis (Bauer, V. J.; Clive, D. R.; Dolphin, D.; Paine, J. B. III; Harris, F. L.; King, M. M.; Loder, J.; Wang, S.-W. C.; Woodward, R. B. J. Am. Chem. Soc. 1983, 105, 6429-6436) (Broadhurst, M. J.; Grigg, R.; Johnson, A. W. J. Chem. Soc. Perkin Trans. 1, 1972, 211-2116 ) involved MacDonald type [3+2] condensations between a functionalized bipyrrole, analogous to 5, and a dicarboxyl substituted tripyrrane, similar to 6, as shown in FIG. 1C. Both, therefore, suffered from the same drawback, namely that the syntheses of these key bipyrrolic and tripyrrolic precursors were long and tedious.